Native Small Airways Secrete Bicarbonate

摘要

Since the discovery of Cl⁻ impermeability in cystic fibrosis (CF) and the cloning of the responsible channel, CF pathology has been widely attributed to a defect in epithelial Cl⁻ transport. However, loss of bicarbonate (HCO3⁻) transport also plays a major, possibly more critical role in CF pathogenesis. Even though HCO3⁻ transport is severely affected in the native pancreas, liver, and intestines in CF, we know very little about HCO3⁻ secretion in small airways, the principle site of morbidity in CF. We used a novel, mini-Ussing chamber system to investigate the properties of HCO3⁻ transport in native porcine small airways (∼ 1 mm φ). We assayed HCO3⁻ transport across small airway epithelia as reflected by the transepithelial voltage, conductance, and equivalent short-circuit current with bilateral 25-mM HCO3⁻ plus 125-mM NaGlu Ringer’s solution in the presence of luminal amiloride (10 μM). Under these conditions, because no major transportable anions other than HCO3⁻ were present, we took the equivalent short-circuit current to be a direct measure of active HCO3⁻ secretion. Applying selective agonists and inhibitors, we show constitutive HCO3⁻ secretion in small airways, which can be stimulated significantly by β-adrenergic– (cAMP) and purinergic (Ca²⁺) -mediated agonists, independently. These results indicate that two separate components for HCO3⁻ secretion, likely via CFTR- and calcium-activated chloride channel–dependent processes, are physiologically regulated for likely roles in mucus clearance and antimicrobial innate defenses of small airways.